1. Field of the Invention
The present invention relates to methods for treating solid tumors, in particular those pertaining to the extended release of an antineoplastic agent from biodegradable compositions.
2. Description of the Prior Art
Antineoplastic agents, such as paclitaxel, have been used to treat solid tumors of various types. For example, those in the art have attempted to administer a variety of antineoplastic agents into the tumor itself (“intralesionally”, also called “intratumorally”) in the form of an aqueous slurry. See Luck et al., U.S. Pat. No. 4,978,332. However, such water-based compositions also require the presence of a vasoconstrictive drug to localize the action of the agent.
An opposite approach has also been taken by formulating a water immiscible, fatty acid ester matrix for intratumoral injection, e.g., of paclitaxel. See WO 95/17901 published 6 Jul. 1995 and Brown et al., U.S. Pat. No. 5,573,781. However, the controlled intratumoral release of the antineoplastic agent in a lipid carrier over a prolonged period of time, for example, at least three or four weeks, has not been disclosed.
Thus, there exists a need for a method of effecting the in vivo, controlled release of a variety of different antineoplastic agents into a solid tumor, whether they are small hydrophobic drugs, such as paclitaxel, or large and bulky bio-macromolecules, such as therapeutically useful proteins. The effective release of the antineoplastic agent preferably occurs without requiring the presence of significant amounts of a physiologically acceptable fluid vehicle, such as normal saline or a water-immiscible organic solvent.
Biocompatible polymeric materials have been used in various therapeutic drug delivery and medical implant applications. If a medical implant is intended for use as a drug delivery or other controlled-release system, using a biodegradable polymeric carrier is one effective means to deliver the therapeutic agent locally and in a controlled fashion, see Langer et al., “Chemical and Physical Structures of Polymers as Carriers for Controlled Release of Bioactive Agents”, J. Macro. Science, Rev. Macro. Chem. Phys., C23(1), 61-126 (1983). In this way, less total drug is required, and toxic side effects can be minimized.
Polymers have been used for some time as carriers of therapeutic agents to effect a localized and sustained release. See Leong et al., “Polymeric Controlled Drug Delivery”, Advanced Drug Delivery Rev., 1:199-233 (1987); Langer, “New Methods of Drug Delivery”, Science, 249:1527-33 (1990) and Chien et al., Novel Drug Delivery Systems (1982). Such delivery systems offer the potential of enhanced therapeutic efficacy and reduced overall toxicity. Examples of classes of synthetic polymers that have been studied as possible solid biodegradable materials include polyesters (Pitt et al., “Biodegradable Drug Delivery Systems Based on Aliphatic Polyesters: Applications to Contraceptives and Narcotic Antagonists”, Controlled Release of Bioactive Materials, 19-44 (Richard Baker ed., 1980); poly(amino acids) and pseudo-poly(amino acids) (Pulapura et al. “Trends in the Development of Bioresorbable Polymers for Medical Applications”, J. Biomaterials Appl., 6:1, 216-50 (1992); polyurethanes (Bruin et al., “Biodegradable Lysine Diisocyanate-based Poly(Glycolide-co-ε Caprolactone)-Urethane Network in Artificial Skin”, Biomaterials, 11:4, 291-95 (1990); polyorthoesters (Heller et al., “Release of Norethindrone from Poly(Ortho Esters)”, Polymer Engineering Sci., 21:11, 727-31 (1981); and polyanhydrides (Leong et al., “Polyanhydrides for Controlled Release of Bioactive Agents”, Biomaterials 7:5, 364-71 (1986).
More specifically, Walter et al., Neurosurgery, 37:6, 1129-45 (1995) discloses the use of the polyanhydride PCPP-SA as a solid carrier for intratumoral administration. Others have used poly(lactic acid) as intratumoral solid carriers, for example, as needles for injection directly into the lesion. See Kaetsu et al., J. Controlled Release, 6:249-63 (1987); and Yamada et al., U.S. Pat. No. 5,304,377.
However, others have encountered problems with these materials. Paclitaxel has been encapsulated in poly(epsilon-caprolactone), but only about 25% of the drug was released over 6 weeks in in vitro assays. Dordunoo et al., “Taxol Encapsulation in Poly(epsilon-caprolactone) Microspheres”, Cancer Chemotherapy & Pharmacology, 36:279-82 (1995). Poly(lactic-co-glycolic acid) microspheres have been used for the encapsulation of paclitaxel and exhibited a relatively constant release rate over three weeks in vitro, but these formulations were not evaluated in vivo. Wang et al., “Preparation and Characterization of Poly(lactic-co-glycolic acid) Microspheres for Targeted Delivery of a Novel Anticancer Agent, Taxol”, Chemical & Pharmaceutical Bulletin, 44:1935-40 (1996). Paclitaxel has also been encapsulated in polyanhydride discs, but the resulting release rate has been described as too slow for clinical utility. Park et al., “Biodegradable polyanhydride Devices of Cefaxolin Sodium, Bupivacaine, and Taxol for Local Drug Delivery: Preparation and Kinetics and Mechanism of in vitro Release”, J. of Controlled Release, 52:179-89 (1998).
Polymers having phosphate linkages, called poly(phosphates), poly(phosphonates) and poly(phosphites), are known. See Penczek et al., Handbook of Polymer Synthesis, Chapter 17: “Phosphorus-Containing Polymers”, (Hans R. Kricheldorf ed., 1992). The respective structures of these three classes of compounds, each having a different side chain connected to the phosphorus atom, are as follows: 
The versatility of these polymers comes from the versatility of the phosphorus atom, which is known for a multiplicity of reactions. Its bonding can involve the 3p orbitals or various 3s-3p hybrids; spd hybrids are also possible because of the accessible d orbitals. Thus, the physico-chemical properties of the poly(phosphoesters) can be readily changed by varying either the R or R′ group. The biodegradability of the polymer is due primarily to the physiologically labile phosphoester bond in the backbone of the polymer. By manipulating the backbone or the side chain, a wide range of biodegradation rates are attainable.
An additional feature of poly(phosphoesters) is the availability of functional side groups. Because phosphorus can be pentavalent, drug molecules or other biologically active substances can be chemically linked to the polymer. For example, drugs with —O-carboxy groups may be coupled to the phosphorus via a phosphoester bond, which is hydrolyzable. See, Leong, U.S. Pat. Nos. 5,194,581 and 5,256,765. The P-O-C group in the backbone also lowers the glass transition temperature of the polymer and, importantly, confers solubility in common organic solvents, which is desirable for easy characterization and processing.
Copending U.S. patent application Ser. No. 09/053,648 filed Apr. 2, 1998, which corresponds to PCT/US98/0681 (published Oct. 8, 1998 as WO 98/44021), discloses biodegradable terephthalate polyester-poly(phosphate) compositions. Copending patent application Ser. No. 09/053,649 filed Apr. 2, 1998, which corresponds to PCT/US98/06380 (published Oct. 8, 1998 as WO 98/44020), discloses biodegradable compositions containing polymers chain-extended by phosphoesters. Further, copending application Ser. No. 09/070,204 filed Apr. 30, 1998, which corresponds to PCT/US98/09185, discloses biodegradable compositions comprising poly(cycloaliphatic phosphoester) compounds. However, none of these disclosures suggests the specific use of biodegradable poly(phosphoester) compositions for the intratumoral treatment of solid tumors.
Thus, there remains a need for new methods and materials for the difficult problem of successfully treating tumors with a minimum of toxicity and avoiding prolonged courses of periodic re-dosing.